Milnacipran (cis-2-amino methyl-N,N-diethyl-1-phenyl cyclopropane carboxamide) is a psychoactive drug, which is a selective norepinephrine and serotonin reuptake inhibitor. It is used for the treatment of clinical depression and chronic pain especially fibromyalgia.
Milnacipran was first disclosed in U.S. Pat. No. 4,478,836. Milnacipran is currently available as Savella® immediate release tablets in USA and is used for the management of fibromyalgia.
Milnacipran has demonstrated numerous adverse reactions in human clinical trials with tolerability decreasing with increasing dose (Puech A. et al., 1997, Int. Clin. Psychopharm, 12:99-108). Milnacipran may induce a locally mediated nausea via gastric irritation and the rapid onset of nausea was observed even prior to achieving peak plasma levels. An immediate release formulation of Milnacipran may not be suitable for a once-daily dosing regimen for treatment of depression and other related diseases due to Milnacipran's relatively short, half-life, which is 8 hours approximately.
Moreover, the currently available immediate release formulation of Milnacipran is not ideal for the treatment of health conditions that require Milnacipran doses equal or above 100 mg/day given either as once a day or twice a day due to the high incidence of treatment-emergent side effects that lead to poor patient tolerance. Higher doses are required in the treatment of severe depression and other associated disorders. Milnacipran dosing regime of 100-250 mg daily was recently reported for the treatment of fibromyalgia (U.S. Pat. No. 6,602,911). It would be very difficult to reach the upper limits of the dose range using the currently available formulation due to the dose related treatment, emergent side effects and the need to titrate over a long period to reach the required dose.
Various approaches have been tried to develop controlled release pharmaceutical compositions of Milnacipran in order to lower the incidence and intensity of side effects, especially for higher dosages, and lower or reduce the frequency of dosing.
U.S. Pat. No. 6,699,506 discloses a pharmaceutical composition with prolonged release, for oral administration of a single daily dose of 60 to 140 mg of Milnacipran, having a multi-particulate form containing a plurality of microgranules each comprising an active microsphere containing a saccharose and/or starch nucleus of a size between 200 and 2000 μm and containing 150 to 1000 μm of Milnacipran and a binding agent, each microgranule being coated with a film having a base of at least one polymer insoluble in water but permeable to physiological liquids.
WO 2006/132307 provides a stabilized Milnacipran-containing composition in which Milnacipran or a salt thereof is allowed to exist in a porous carrier, packing a powder containing Milnacipran or a salt thereof in an HPMC capsule, or combining an additive which does not cause an interaction with Milnacipran with time.
WO 2006/088305 discloses a gastric-retentive controlled release mono-matrix tablet composition, comprising: a) at least one pharmacologically active substance; b) hydrogel-forming materials consisting of polyethylene oxide and at least one component selected from poloxamers and colloidal silica; and c) a carbon dioxide-generating material. The composition of the present invention floats in gastric juice and can continuously release the active substance in the stomach at a constant rate for at least 2 hours.
US 2004/0132826 and US 2006/0024366 provide an extended release dosage unit of Milnacipran (optionally containing the immediate release portion) coated with delayed release coating. The Milnacipran composition, when administered orally, first passes through the stomach releasing from zero to less than 10% of the total Milnacipran dose and then enters the intestines where drug is released slowly over an extended period of time.
Although above mentioned patents and patent applications provide controlled release dosage forms, but production of dosage forms of these references is lengthy, expensive process or requires specialized equipments or techniques.
There exists a need to develop a novel controlled release pharmaceutical composition comprising Milnacipran or pharmaceutically acceptable salts thereof, which offers advantages like simple manufacturing process, compact dosage form, use of conventional manufacturing equipment, high throughput, easy scale-up, economic, etc.
Additionally there is a need to provide a controlled release pharmaceutical composition comprising Milnacipran or pharmaceutically acceptable salts thereof, wherein composition provides complete dissolution between 8 to 20 hrs or the pharmaceutical composition of the present invention can be suitably designed to provide controlled release compositions that control release over prolonged periods of time, at least for 12 hours after oral administration. Thus the present invention provides a novel controlled release pharmaceutical composition comprising Milnacipran or pharmaceutically acceptable salts thereof, to control release over prolonged periods of time.